The present invention relates to novel pyrimidinedione derivatives, which are useful as an antiviral agent, particularly for treating acquired immunodeficiency syndrome (AIDS), a process for the preparation thereof and a pharmaceutical composition containing same as an active ingredient.
Various compounds such as AZT (3xe2x80x2-azido-3xe2x80x2-deoxythymidine), DDC (2xe2x80x2,3xe2x80x2-dideoxycytidine), DDI (2xe2x80x2,3xe2x80x2-dideoxyinosine), D4T (3xe2x80x2-deoxy-2xe2x80x2,3xe2x80x2-didehydrothymidine) 3TC(lamivudine), Ziagen, Nevirapine, Sustiva, Delavirdine, Indinavir, Ritonavir, Viracept, Saquinavir and Agenerase have been reported to have the ability, albeit limited, to inhibit the reproduction of AIDS virus. However, they are also known to cause undesirable side effects due to their toxicity as well as to induce the mutation of the virus, thereby increasing the resistance of the virus.
In order to minimize such problems, therefore, many attempts have been made. For example, there have been reported 2,4-pyrimidinedione derivatives having 1-alkoxymethyl substituents {J. Med. Chem., 35, 4713 (1992); J. Med. Chem., 35, 337 (1992); J. Med. Chem., 34, 1508 (1991); J. Med. Chem., 34, 1394 (1991); J. Med. Chem., 34, 349 (1991); Molecular Pharm., 39, 805 (1991); Tet. Lett., 35, 4531 (1994); J. Med. Chem., 38, 2860 (1995); Nucleosides and Nucleotides, 14, 575 (1995); J. Med. Chem., 39, 2427 (1996); J. Med. Chem., 42, 4500 (1999); EP 0,449,726 A1; EP 0,420,763 A2; U.S. Pat. No. 5,278,167; U.S. Pat. No. 5,318,972; U.S. Pat. No. 5,461,060; WO95/18109 A1; and U.S. Pat. No. 5,112,835}; 1-allyl or propargyl substituents (U.S. Pat. No. 5,747,500); and 1-cyclopentenylmethylene substituents (U.S. Pat. No. 5,922,727). Although these compounds exhibit improved activity against human immunodeficiency virus (HIV), there exists a need to develope non-toxic compounds having even higher potency against both wild-type and mutant HIV.
Accordingly, it is a primary object of the present invention to provide a novel compound having superior antiviral activity against both wild-type and mutant HIV-1 as well as reduced toxicity.
It is another object of the present invention to provide a pharmaceutical composition containing same.
It is a further object of the present invention to provide a process for the preparation of said novel compound.
In accordance with one aspect of the present invention, there is provided a novel 2,4-pyrimidinedione compound of formula(I) or a pharmaceutically acceptable salt thereof: 
wherein:
R1 is a C6-10 aryl or C3-10 heteroaryl group optionally having one or more substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkyl substituted with one or more halogen atoms, C3-6 cycloalkyl, cyano, nitro, hydroxy, thiohydroxy, azido, C1-6 alkoxy, oximino, C1-3 alkyloximino, Oxe2x80x94(C1-6 alkyl)-substituted oximino, C1-6 alkylcarbonyl, C3-6 cycloalkylcarbonyl, hydroxymethyl, azidomethyl, C1-6 alkoxymethyl, C1-6 acyloxymethyl, carbamoyloxymethyl, aminomethyl, Nxe2x80x94(C1-3 alkyl)aminomethyl, N,N-di(C1-3 alkyl)aminomethyl, carboxy, C1-6 alkoxycarbonyl, aziridine, amino, hydroxyethylamino, cyclopropylamino, C1-6 alkylamino, di(C1-6 alkyl)amino, trifluoroacetamido, C1-6 acylamido, carbamoyl, hydroxyethylcarbamoyl, cyclopropylcarbamoyl, C1-6 alkylcarbamoyl, di(C1-6 alkyl)carbamoyl, aminocarbamoyl, dimethylaminocarbamoyl, hydrazino, 1,1-dimethylhydrazino, imidazolyl, triazolyl and tetrazolyl; a tetrahydropyridyl or piperidyl group optionally substituted with a c1-6 alkyl or c1-6 alkoxycarbonyl group; a tetrahydropyranyl group; or a tetrahydrofuryl group;
R2 is hydrogen, halogen, nitro, cyano, C1-3 alkoxycarbonyl, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-3 alkylcarbamoyl, di(C1-3 alkyl)carbamoyl, C1-6 alkyl, C3-6 cycloalkyl or benzyl;
R3 and R4 are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino, acetamido, trifluoroacetamido, azido, C1-3 alkyl, C1-3 alkyl substituted with one or more halogen atoms, C1-3 alkoxycarbonyl, carbamoyl, C1-3 alkylcarbamoyl, di(C1-3 alkyl)carbamoyl or C1-3 alkoxy;
A is O or S; and
Z is O, S, Cxe2x95x90O, NH or CH2.
Among the compounds of formula(I) of the present invention, the preferred are those wherein R1 is a phenyl, pyridyl or N-oxopyridyl group optionally having one or more substituents as listed in formula(I).
The 2,4-pyrimidinedione compound of formula(I) may be prepared by coupling a compound of formula(II) with a compound of formula(III), as shown in the Reaction Scheme A: 
wherein:
R1, R2, R3, R4, A and Z have the same meanings as defined in formula(I) above;
Zxe2x80x2 is same as Z with the proviso that when A is oxygen, it can be a acetamido group; and
Y is a suitable leaving group, e.g., halogen, methanesulfonyl, toluenesulfonyl or trifluoromethanesulfonyl.
In Reaction Scheme A, the above reaction may be conducted in a solvent in the presence of a base at a temperature ranging from xe2x88x9210 to 100xc2x0 C., wherein the molar ratio of the compound of formula(II) to the compound of formula(III) may range from 1:0.8 to 1:1.2. Representative examples of the base include lithium hydride, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate and the like. Suitable for use in this reaction is a polar solvent such as acetonitrile, hexamethylphosphoramide (HMPA), dimethylsulfoxide (DMSO) and dimethylformamide(DMF).
The compounds of formula(II) may in some cases be prepared in accordance with the procedure disclosed in U.S. Pat. No. 5,747,500. Alternatively, the compounds of formula(II) may be advantageously prepared in some special cases by the procedure illustrated in Reaction Scheme B: 
In accordance with the method (i) in Reaction Scheme B, a compound of formula(IV) which may be prepared by way of a known method disclosed in, e.g., Ber., 52B, 869 (1919) and J. Med. Chem., 7, 808 (1964), is subjected to a coupling reaction with an arylformamide derivative in a polar solvent, e.g., dimethylformamide, in the presence of a strong base, e.g., sodium hydride, under a nitrogen atmosphere to provide a compound of formula(V) (Step (a)). The compound of formula (V) is reacted with sodium methoxide in methanol to give a compound of formula(VI) (Step (b)). Then, the compound of formula(VI) is demethylated and acetylated by the action of acetylbromide to provide a compound of formula(II-a) (Step (c)).
In the method (ii) of Reaction Scheme B, the compound of formula (IV) is reacted with a arylacetonitrile derivative in a polar solvent, e.g., dimethylformamide, in the presence of a base, e.g., sodium hydride, to provide a compound of formula(VII) (Step (d)), which is reacted with sodium methoxide in methanol to give a compound of formula(VIII) (Step (e)). Thereafter, the compound of formula(VIII) is reacted with a base, e.g., sodium hydride, in a polar solvent, e.g., dimethylformamide, in the presence of oxygen to provide a compound of formula(IX) (Step (f)), which is hydrolyzed with an acid, e.g., hydrochloric acid, to provide a compound of formula(II-b) (Step (g)).
Each of the compounds of formula(II-a) and (II-b) may be converted to one of the compounds of formula(II) containing various substituents via further reactions.
In this regard, in accordance with another aspect of the present invention, there is provided a compound of formula(II): 
wherein:
Rxe2x80x22 is ethyl or isopropyl;
Rxe2x80x23 is nitro, amino, acetamido, trifluoroacetamido or C1-3 alkoxycarbonyl;
Rxe2x80x24 is methyl or halogen; and
Zxe2x80x3 is Cxe2x95x90O, NH or acetamido.
Exemplary compounds of formula(I) of the present invention which can be prepared in accordance with the methods described above are listed in the following Table 1:
Furthermore, the present invention encompasses, within its scope, pharmaceutically acceptable salts of the 2,4-pyrimidinedione compounds of formula(I). Suitable pharmaceutically acceptable salts of the compounds of formula(I) possessing strong antiviral activity against wild-type and mutant HIV-1 may include alkali or alkaline earth metal salts, e.g., sodium, potassium, magnesium and calcium salts thereof.
The present invention also includes within its scope pharmaceutical compositions comprising one or more of the compounds of formula(I) or their above-mentioned salts as the active ingredient, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary.
The pharmaceutical compositions of the invention may be formulated for administration orally or by injection. The composition for oral administration may take various forms such as tablets and gelatin capsules, which may contain conventional additives such as a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine), a lubricant (e.g., silica, talc, stearic acid or its magnesium and calcium salts and polyethylene glycol). In the case of the tablet form, the composition may further comprise a binder (e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and polyvinyl pyrrolidone) and optionally a disintegrant (e.g., starch, agar and alginic acid or its sodium salt), absorbent, colorant, flavor, sweetener and the like. The composition for injection may be an isotonic solution or a suspension.
The composition may be sterilized and/or contain an adjuvant such as a preservative, stabilizer, wetting agent, emulsifier, a salt for controlling an osmotic pressure and/or a buffer solution, and other pharmaceutically effective materials.
The pharmaceutical compositions can be prepared by a conventional mixing, granulating or coating method and may contain preferably about 0.1 to 75%, more preferably about 1 to 50% of the active ingredient of this invention. The unit dosage of the composition suitable for administering a person weighing about 50 to 70 kg may contain about to 200 mg of the active ingredient.
The following Preparations and Examples are given for the purpose of illustration only and are not intended to limit the scope of the invention.
In the Preparations and Examples, unless otherwise specified, the evaporation was conducted under reduced pressure, preferably under a pressure ranging from about to 100 mmHg.
The compounds of formula(II) having the structures (A) to (U), (II-a-1), (II-a-2) and (II-b-1) shown in Table 2 together with their melting points and NMR data were used in preparing respective compounds of formula (I) of the present invention.
Each of the compounds having the specified structures (A) to (U) was prepared in accordance with the procedure described in U.S. Pat. No. 5,747,500.
Step 1) Synthesis of 2,4-Dichloro-5-isopropyl-6-(3xe2x80x2,5xe2x80x2-dimethylphenylformylamido)pyrimidine
To a magnetically stirred DMF solution (80 ml) of 3,5-dimethylformaniline (8.94 g, 60 mmol) cooled in an ice bath, 60% sodium hydride dispersion (2.88 g, 72 mmol) was added portionwise under a nitrogen atmosphere. After 10 min, 5-isopropyl-2,4,6-trichloropyrimidine (16.2 g, 72 mmol) was added thereto and the reaction mixture was allowed to warm to room temperature, followed by stirring for 24 hr. Ether was then added to the reaction mixture, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-ether:hexane=1:15) to afford 3.3 g (yield 17%) of the title compound as a white solid.
M.p.: 151 to 153xc2x0 C.; 1H-NMR (200 MHz, CDCl3) xcex4 1.12-1.24 (6H, m), 2.30 (6H, s), 3.22 (1H, m), 6.72 (2H, s), 6.96 (1H, s), 8.70 (1H, s); m/z (EI) 338 (M+).
Step 2) Synthesis of 2,4-Dimethoxy-5-isopropyl-6-(3xe2x80x2, 5xe2x80x2-dimethylphenylamino)pyrimidine
Sodium (1.02 g, 44 mmol) was added portionwise to a stirred anhydrous methanol (40 ml) at room temperature under a nitrogen atmosphere to prepare sodium methoxide solution. The compound obtained in Step 1) (3 g, 8.88 mmol) was added to the solution and the mixture was refluxed for 4 hr. The reaction mixture was allowed to cool to room temperature and neutralized with excess ammonium chloride. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-ethyl acetate:hexane=1:15) to afford 2.69 g (yield 97%) of the title compound as a white solid.
M.p.: 126 to 127xc2x0 C.; 1H-NMR (200 MHz, CDCl3) xcex4 1.31 (6H, d, J=7.1 Hz), 2.31 (6H, s), 3.12 (1H, m), 3.92 (3H, s), 3.93 (3H, s), 6.44 (1H, s), 6.70 (1H, s), 7.21 (2H, s); m/z (EI) 301 (M+).
Step 3) Synthesis of 5-Isopropyl-6-(3xe2x80x2,5xe2x80x2-dimethylphenylacetamido)-2,4-pyrimidinedione
The compound obtained in Step 2) (2.6 g, 8.6 mmol) was refluxed with acetyl bromide (30 ml) for 19 hr. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromat ography (eluent-ethyl acetate:hexane=2:1) to afford 2.6 g (yield 96%) of the title compound as a white solid.
The procedure of Preparation 22 was repeated using 5-ethyl-2,4,6-trichloropyrimidine in place of 5-isopropyl-2,4,6-trichloropyrimidine to prepare the title compound.
Step 1) Synthesis of 2,4-Dichloro-5-isopropyl-6-(xcex1-cyano-3xe2x80x2-nitro-5xe2x80x2-methylbenzyl)pyrimidine
To a magnetically stirred DMF solution (30 ml) of 3-nitro-5-methylphenylacetonitrile (2.64 g, 15 mmol) and 5-isopropyl-2,4,6-trichloropyrimidine (4.05 g, 18 mmol) cooled in an ice bath, 60% sodium hydride dispersion (1.15 g, 30 mmol) was added portionwise under a nitrogen atmosphere. After stirring for 2 hr, the reaction mixture was allowed to warm to room temperature and stirred for 16 hr. The reaction mixture was then neutralized with aqueous ammonium chloride and ethyl ether was added thereto. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-ethyl acetate:hexane=1:4) to afford 3.99 g (yield 73%) of the title compound as a white solid.
M.p.: 124 to 125xc2x0 C.; 1H-NMR (200 MHz, CDCl3) xcex4 1.23 (3H, d, J=7.2 Hz), 1.38 (3H, d, J=7.2 Hz), 2.51 (3H, s), 3.34 (1H, m), 5.60 (1H, s), 7.57 (1H, s), 7.99 (1H, s), 8.07 (1H, s); m/z (EI) 365 (M+).
Step 2) Synthesis of 2,4-Dimethoxy-5-isopropyl-6-(xcex1-cyano-3xe2x80x2-nitro-5xe2x80x2-methylbenzyl)pyrimidine
To a stirred anhydrous methanol solution (60 ml) of the compound obtained in Step 1) (3.65 g, 10 mmol), sodium methoxide (3.24 g, 60 mmol) was added at room temperature under a nitrogen atmosphere and refluxed for 24 hr. The reaction mixture was then allowed to cool to room temperature and neutralized with excess ammonium chloride. After removing the solvent, the resulting residue was purified by flash chromatography (eluent-ether:hexane=1:3) to afford 1.8 g (yield 50%) of the title compound as a light yellow solid.
M.p.: 134 to 135xc2x0 C. 1H-NMR (200 MHz, CDCl3) xcex4 1.15 (3H, d, J=6.7 Hz), 1.20 (3H, d, J=6.7 Hz), 2.49 (3H, s), 3.05 (1H, m), 4.00 (3H, s), 4.01 (3H, s), 5.48 (1H, s), 7.62 (1H, s), 8.00 (2H, s); m/z (EI) 356 (M+).
Step 3) Synthesis of 2,4-Dimethoxy-5-isopropyl-6-(3xe2x80x2-nitro-5xe2x80x2-methylbenzoyl)pyrimidine
To a stirred DMF solution (20 ml) of the compound obtained in Step 2) (1.7 g, 4.7 mmol), 60% sodium hydride dispersion (283 mg, 7.1 mmol) was added at room temperature under a nitrogen atmosphere. The mixture was then stirred in the presence of oxygen. After 5 hr, the reaction mixture was neutralized with ammonium chloride and ethyl ether was added thereto. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-dichloromethane:hexane=97:3) to afford 1.039 (yield 62%) of the title compound as a white solid.
M.p.: 111 to 112xc2x0 C.; 1H-NMR (200 MHz, CDCl3) xcex4 1.21 (6H, d, J=6.9 Hz), 2.54 (3H, s), 2.88 (1H, m), 3.93 (3H, s), 4.09 (3H, s), 8.05 (1H, s), 8.27 (1H, s), 8.44 (1H, s); m/z (EI) 345 (M+).
Step 4) Synthesis of 5-isopropyl-6-(3xe2x80x2-nitro-5xe2x80x2-methylbenzoyl)-2,4-pyrimidinedione
The compound obtained in Step 3) (630 mg, 1.8 mmol) was refluxed with conc. hydrochloric acid (6 ml) for 4 hr and the reaction mixture was allowed to cool to room temperature. The precipitate was then collected, washed with distilled water and hexane, and dried to give 560 mg (yield 98%) of the title compound as a white solid.